Abstract Overnutrition, or excess caloric intake, positively correlates with type 2 diabetes, obesity, cardiovascular disease, fatty liver disease, and reduced lifespan. Because this phenomenon is less than 100 years old, humans have not yet undergone the pressure to adapt to caloric excess. Our goal is to discover new genes and pathways that are able to protect from the negative effects of high- calorie diets. To treat the sequelae of overnutrition, researchers and physicians have typically targeted specific steps in metabolic pathways that are expected to reduce pathophysiology, with limited success. This proposal outlines an alternative approach, which is to subject an outbred population to laboratory adaptation to overnutrition. Drosophila represents an ideal model for such studies owing to its rapid generation time, frequent meiotic recombination during sexual reproduction, ease of genetic manipulation, and well-characterized genome. This proposal tests the hypothesis that this evolve-and-resequence strategy will enrich the genome for variants that promote fitness in the face of caloric excess. Next-generation sequencing of the adapted genomes will reveal which quantitative trait loci are beneficial to health, focusing on single nucleotide polymorphisms. RNA- sequencing will also contribute to an understanding of how these variants might function to control gene expression. High-powered, correlative genomic analyses and bioinformatics will be used to identify genome variants that increase fly fitness on high-sugar diets. These variants will be introduced into nave flies to determine which changes are truly protective against the sequelae of caloric excess. The successful completion of these aims may identify drug targets for those suffering from the complications of morbid obesity due to overnutrition.